ABSTRACT Background: We propose to elucidate molecular mechanisms mediated by High Mobility Group A1 (HMGA1) chromatin remodeling proteins during colorectal carcinogenesis. The HMGA1 gene is highly expressed during embryogenesis, but silenced postnatally in most adult tissues. HMGA1 is also overexpressed in diverse, poorly differentiated cancers and high levels portend adverse outcomes. HMGA1 proteins modulate gene expression by ?opening? chromatin and recruiting transcriptional complexes to DNA. While it is clear that chromatin regulators help to govern nuclear architecture and cell fate decisions, the underlying mechanisms are poorly understood. Here, we focus on HMGA1 in colorectal cancer (CRC). Our scientific premise that HMGA1 fosters tumor progression in CRC is based on the following preliminary results: 1) HMGA1 is highly overexpressed in CRC compared to non-malignant colonic epithelium, 2) Silencing HMGA1 blocks oncogenic properties, prevents metastatic progression, and depletes cancer stem cells in preclinical CRC models, 3) In transgenic mice, Hmga1 overexpression: a) induces hyperproliferation, aberrant crypt formation, and premalignant polyposis in small and large intestines, and, b) expands the small intestinal stem cell (ISC) pool by amplifying Wnt signals (Xian et al, Nature Comm; 2017), 5) Surprisingly, Hmga1 also helps to ?build? a stem cell niche by inducing Sox9 to generate Paneth cells, which support and nurture small ISCs, 6) HMGA1 and SOX9 are positively correlated in human colon epithelium and both become markedly up-regulated in colon cancer, and, 7) Inflammatory signals and procarcinogenic bacteria associate with Hmga1 expression in preclinical tumor models. Together, these intriguing results support the following hypotheses: 1) Hmga1 is required for normal stem cell function and tissue homeostasis in colonic epithelium, 2) Deregulated HMGA1 disrupts this equilibrium and drives carcinogenesis and tumor progression through aberrant changes in chromatin structure and gene expression, 3) Inflammatory signals and specific pro-carcinogenic bacteria induce HMGA1 to drive tumor progession, and, 4) Identifying mechanisms linked to HMGA1 overexpression will reveal novel pathways that could be modulated to treat, or even prevent, colon carcinogenesis. Aims/Approach: To test this, we propose the following Specific Aims: 1) To define oncogenic and stem cell phenotypes dependent upon HMGA1 in colonic epithelium, 2) To elucidate epigenetic alterations and genetic pathways through which HMGA1 functions during carcinogenesis, and, 3) To determine whether targeting Hmga1 is effective in mitigating or preventing colon carcinogenesis in preclinical models. Impact: We expect to elucidate mechanisms that induce HMGA1 as well as downstream pathways governed by HMGA1 in CRC. This work could reveal a new paradigm for colon cancer pathogenesis and lead to novel approaches to treat, or even prevent, this formidable cancer.